Systematic Review of Intestinal Microbiota Transplantation 2011

R E V I E W A R T I C L E

Systematic Review of Intestinal MicrobiotaTransplantation (Fecal Bacteriotherapy) forRecurrent Clostridium difficile Infection

Ethan Gough,1 Henna Shaikh,2 and Amee R. Manges1,3

Departments of 1Epidemiology Biostatistics and Occupational Health, and 2Biology, McGill University, and 3Research Institute of the McGill UniversityHealth Centre, Montreal, Quebec, Canada

Clostridium difficile infection (CDI) is a gastrointestinal disease believed to be causally related to perturbations

to the intestinal microbiota. When standard treatment has failed, intestinal microbiota transplantation

(IMT) is an alternative therapy for patients with CDI. IMT involves infusing intestinal microorganisms

(in a suspension of healthy donor stool) into the intestine of a sick patient to restore the microbiota. However,

protocols and reported efficacy for IMT vary. We conducted a systematic literature review of IMT treatment for

recurrent CDI and pseudomembranous colitis. In 317 patients treated across 27 case series and reports, IMT

was highly effective, showing disease resolution in 92% of cases. Effectiveness varied by route of instillation,

relationship to stool donor, volume of IMT given, and treatment before infusion. Death and adverse events were

uncommon. These findings can guide physicians interested in implementing the procedure until better

designed studies are conducted to confirm best practices.

Clostridium difficile infection (CDI) is a gastrointestinal

disease believed to be causally related to perturbations to

the intestinal microbiota [1]. The term microbiota refers

to the community of microorganisms that inhabit

a particular region of the body [2]. In the human gut,

there are 300500 species of microorganisms (in-testinal microbiota), with roughly 1012 bacterial cells per

gram of stool [3]. These organisms aid in several func-

tions, including digestion of complex carbohydrates,

energy storage, immune functions, and protection

against invasion by pathogens [3]. Existing evidence

shows that certain classes of antimicrobials have pro-

found effects on the intestinal microbiota [4]. The

widely accepted model for C. difficile pathogenesis is that

the use of broad spectrum antimicrobials alters the

balance of the intestinal microbiota, allowing patho-

genic strains of C. difficile to infect the intestine [13].

Primary episodes of CDI are treated with metroni-

dazole or vancomycin after cessation of the antibiotic

believed to be related to the infection [4], and up to 35%

of patients treated experience a recurrence of symptoms

after initial improvement [5, 6]. Up to 65% of these

patients develop a chronic recurrent pattern of disease

(recurrent CDI) [1, 5]. Recurrent CDI is typically trea-

ted using a tapered (31% recurrence rate) or pulsed

(14% recurrence rate) regimen of metronidazole or

vancomycin [4, 5]. Given the poor treatment outcomes

for CDI, especially recurrent CDI, it is not surprising

that investigation of treatment alternatives has contin-

ued over several decades [2, 4, 79].

One potential alternative to standard therapy is the use

of indigenous intestinal microorganisms from a healthy

donor (via infusion of a liquid suspension of stool) to

restore the intestinal microbiota of a diseased individual.

First documented in humans in 1958 [10], fecal bacter-

iotherapy, also called intestinal microbiota trans-

plantation (IMT), may be a useful treatment for CDI

through restoration of the intestinal microbiota [5].

Received 27 April 2011; accepted 16 August 2011.Correspondence: Amee R. Manges, MPH, PhD, McGill University, Department of

Epidemiology, Biostatistics and Occupational Health, 1020 Pine Ave W, Montreal,QC H3A1A2, Canada ([email protected]).

Clinical Infectious Diseases 2011;53(10):9941002 The Author 2011. Published by Oxford University Press on behalf of theInfectious Diseases Society of America. All rights reserved. For Permissions,please e-mail: [email protected]/2011/5310-0004$14.00DOI: 10.1093/cid/cir632

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IMT has not been widely adopted as a therapeutic tool probably

due to concerns regarding safety and acceptability [11]. Despite

these concerns, the procedure has been performed in a growing

number of patients throughout the world. In addition to

treating CDI, IMT has also been used to treat pseudomem-

branous colitis (PMC), believed to be caused by C. difficile

toxins, inflammatory bowel disease and irritable bowel syn-

drome (IBS), 2 diseases also believed to be causally related to the

intestinal microbiota [1].

IMT protocols vary with regard to the quantity of donor stool

used, preparation of recipients, methods for infusion of donor

stool, and measurement of outcomes. To our knowledge,

4 publications have reviewed the literature on the use of this

procedure [1, 6, 12, 13], but none were systematic reviews.

Additionally, we know of only 1 randomized controlled trial

(RCT) currently underway to test the efficacy of IMT in the

treatment of CDI [12]. To summarize the literature on the use of

IMT and provide direction for future investigations of this still

poorly understood intervention, we conducted a systematic review

of fecal transplantation in humans as therapy for CDI and PMC.

METHODS

Search Strategy and Selection CriteriaWe searched Medline, Embase, and Biosis through Ovid (up to

15 April 2011) for publications, in any language, documenting

the infusion of stool from a healthy human donor, into an

unhealthy human subject, as treatment for a specified medical

condition (Supplementary Appendix 1, online only). Publications

of any type were included if they reported original data from

such a procedure for CDI or PMC treatment. Bibliographies

of all identified reviews [1, 58, 1216] and original research

publications were hand searched for additional studies. We

also searched Current Contents, Conference Papers Index,

Papersfirst, and Web of Science for conference proceedings and

abstracts that may not have been indexed in these 3 databases.

Terms from the Ovid search were used as keywords with no

limits, as shown in Supplementary Appendix 2, online only. All

search strings were developed with the assistance of a qualified

librarian.

Two investigators (E. G. and H. S.) independently assessed

titles and abstracts for eligible publications. If eligibility could not

be determined, the full article was retrieved. Publications that did

not report original data on the outcome of the IMT procedure,

reports describing the use of a cultured bacterial suspension

rather than human feces, interviews, and reviews were excluded.

Data Abstraction and AnalysisOnce eligibility was determined, 2 reviewers (E. G. and H. S.)

independently abstracted data from selected publications using

a standardized pretested form. Discrepancies were corrected by

consensus. Data from nonEnglish-language publications were

simultaneously extracted by 2 reviewers (A. R. M. and Kerstin

Tiedemann). The following information was retrieved: number of

patients, patient characteristics (average age, number of men),

transplantation procedures (patient preparation, choice of donor,

dosage, number of infusions, route of instillation, retreatments

offered if treatment failed, duration of follow-up, outcomes

(death, treatment failure, resolution, relapse), and adverse events.

Study period, country, and study design were also abstracted.

Three investigators were emailed for unpublished data [17, 18]

(Thomas Moore unpublished data). One did not respond [17],

and data were no longer available from another [18]. When

multiple publications reported on the same patients [1824], we

analyzed the most recent and complete data [18, 20, 24].

Data of interest were often not reported. Agreement between

independent reviewers on availability of data, and data abstracted,

were computed for 10 key variables using a j statistic. Data were

summarized using Stata software (version 11.0; StataCorp).

Operational DefinitionsThe following operational definitions were used to standardize

data abstraction. A failure was defined as the continued occur-

rence of clinical illness during (1) the period of follow-up sub-

sequent to transplantation but before retreatment or (2) during

the period of follow-up subsequent to retreatment. Resolution

was defined as either complete cessation of clinical symptoms or

diagnostic confirmation of the absence of disease, during the

period of follow-up after transplantation. When multiple in-

fusions were not given as part of a retreatment for failure, they

were counted as part of a single treatment. Resolution after

1 treatment was therefore counted separately from resolution

after retreatment due to failure. A relapse was defined as reso-

lution, with subsequent return of signs and symptoms during

the follow-up period, and was counted only among patients with

resolution. Deaths were recorded as due to the illness or not, as

reported by the authors. Studies varied in the reporting of the

IMT dosage given to patients. To make use of all available in-

formation related to the amount of donor stool patients were

exposed to in a single infusion, stool weight was defined as the

quantity (in grams) of donor stool used to make the IMT sus-

pension, and suspension volume was defined as the volume

(in milliliters) of the IMT suspension infused. Number of in-

fusions was defined as the number of times donor stool was

infused, not including retreatments when treatment failed.

RESULTS

Literature ReviewThe electronic search identified 2054 titles. All titles and ab-

stracts were reviewed. Of the 66 reports selected for full review,

28 were excluded based on eligibility criteria [1, 48, 1116,

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2540] (Figure 1). An additional 11 titles were excluded because

they did not report treatment for CDI or PMC [4144], reported

data from the same subjects as more recent reports [19, 2123],

did not report data on key variables of interest [45], did not

report data disaggregated by diagnosis [46], or could not be

translated [47] (Figure 1).

Characteristics of Included ReportsIn total, 27 unique reports were included in the analysis [10, 17,

18, 20, 24, 4868] (Thomas Moore, unpublished data) (Table 1).

One article provided 2 abstractions [50] resulting in 28 ob-

servations for analysis. Agreement among reviewers on

availability of data and data abstracted was high (median

j value, 0.91 and 0.8, respectively). The majority of reports

were journal articles (70%); followed by letters (15%), ab-

stracts (12%), and unpublished data (3%). Two-thirds (67%)

were case series; the remainder were case reports (data not

shown). Periods of data collection spanned 19571958 to

20012011, providing data on 317 patients (Table 1) from

8 countries. The average patient age was 53 years (range, 295

years), and 39% of patients were male. Follow-up ranged from

36 hours to 5 years. In all studies, patients had diagnoses of

recurrent or relapsing CDI (91%) or PMC (9%) (Table 1).

IMT ProceduresThe majority of patients received the IMT by enema (35%) or by

gastroscope or nasojejunal (NJ) tube (23%) from a donor who

was a relative (66%). Per treatment, approximately half received

1 infusion (range, 148 infusions) and the majority received a

$200-mL IMT suspension (71%) (range, 25-1500 mL) (Table 1),

typically given immediately after preparation (47%). Normal

saline was used to prepare most IMT suspensions (62%).

Where information was provided, all patients received antibi-

otic treatment or another procedure before IMT (Table 2).

Patients with treatment failure or relapse were given IMT re-

treatment (44%), vancomycin or metronidazole (28%), or re-

treatment with antibiotics (3%), or their treatment was not

reported (25%) (data not shown).

Outcomes in Patients Treated for CDINinety-two percent of patients experienced resolution (Table 1),

89% after a single treatment (Table 2), and 5% after retreatment

due to failure or relapse (data not shown). Eleven (4%) experi-

enced a relapse in symptoms. With a single treatment, resolution

rates were lowest with 1 infusion (87.5%); however 23% of these

patients received infusion by gastroscope or NJ tube, which also

showed the lowest resolution rate by route (76%) (Table 2). IMT

Figure 1. Flow diagram of study selection. aThe 27 unique publications provided 28 abstractions. CDI, Clostridium difficile infection; IMT, intestinalmicrobiota transplantation; PMC, pseudomembranous colitis.




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Table 1. Summary of Case Series and Reports of Intestinal Microbiota Transplantation

Reference

Years of

data collection Diagnosis

No. of

patients

Patients with

resolution,

no. (%)aAge, mean

(range), y

Duration of

follow-up,

mean (range)

Stool, g/suspension

volume, mL

Infusions per

treatment

Donor relationship

(no. of patients)

Instillation method

(no. of patients)

Schwan et al [20] 19771983 CDI 1 1 (100.0) 67 1 y NR/450 2 H Enema

Tvede et al [48] NR CDI 2 1 (50.0) 60 (5960) 12 mo 50/500 1 H (1), D (1) Enema

Flotterod et al [49] 19821985 CDI 1 1 (100.0) 64 NR 10/NR 1 H Duodenal endoscope

Paterson et al [50] NR CDI 1 1 (100.0) 39 2 y 200/200 3 H Enema

Paterson et al [50] NR CDI 6 6 (100.0) 56 (3080) NR NR/NR NR R Enema

Lund-Tonnesen et al [18] 19951996 CDI 18 15 (83.3) 64 (2789) 18 mob 510/NR NR UR Colonoscope

Persky et al [51] NR CDI 1 1 (100.0) 60 5 y NR/500 NR H Colonoscope

Borody et al [452] NR CDI/IBD 6 6 (100.0) NR (1159) 8 wk 200300/200300 114 H Enema

Aas et al [53] 19942002 CDI 18 15 (83.3) 73 (5188) 90 d 30/25 1 R (15), UR (3) NJ tube

Jorup- Ronstrom et al [54] NR CDI 5 4 (80.0) 83 (7988) 2 mo (521) NR/30 1 UR Fecal lavage (3),enema (1), NR (1)

Wettstein et al [55] NR CDI 16 15 (93.7) NR (1187) NR (46 wk) 200300/200300 124 R, UR Colonoscopy, enema

Louie et al [56] NR CDI 45 44 (97.7) 62 (3091) 1 y 300500/10001500 13 R (35), UR (10) Rectal catheter

Nieuwdorp et al [57] NR CDI 7 7 (100.0) 67 (4881) 84 d 150/300400 NR S (3), D (4),LA (1), UR (1)

Colonoscope

You et al [58] NR CDI 1 1 (100.0) 69 36 h 45/300 1 D Enema

Hellemans et al [59] NR CDI 1 1 (100.0) 59 4 mo NR/NR 5 B Colonoscope

MacConnachie et al [60] NR CDI 15 12 (80.0) 82 (6895) 16 wk (424) 30/30 1 R NJ Tube

Khoruts et al [61] NR CDI 1 1 (100.0) 61 6 mo 25/250 1 H Colonoscope

Garborg et al [17] 19942008 CDI 40 33 (82.5) 75 (5394) 80 d 50100/200 1 R, UR Gastroscope (38),colonoscope (2)

Rohlke et al [62] 20042009 CDI 19 19 (100.0) 49 (2982) 27 mo (665) NR/200300 12 SP, R, UR Colonoscope

Russell et al [63] NR CDI 1 1 (100.0) 2 6 mo 30/25 NR F NJ tube

Silverman et al [64] NR CDI 7 7 (100.0) 65 (3088) 8.6 mo (414) 50/250 1 R Enema

Yoon et al [24] NR CDI 12 12 (100.0) 66 (3086) NR (3 wk to 8 y) NR/250400 1 SP (8), S (1), D (2),GC (1)

Colonoscope

T. Moore (unpublished) 20012011 CDI 65 64 (98.5) 68 (1889) 30 d (30 d to 5 y) NR/1000 1 SP, P, C, S Enema

Cutolo et al [65] NR PMC/S. aureus 1 1 (100.0) 65 96 d 57/1240 48/59 48c, 24d UR Cantor tube

Eiseman et al [10] 19571958 PMC/S. aureus 4 4 (100.0) 56 (4568) 7 d (311) NR/NR 13 NR Enema

Fenton et al [66] 1974 PMC 1 1 (100.0) 57 NR NR/NR 1 NR Enema

Bowden et al [67] NR PMC 16 13 (81.2) 56 (1485) NR (5 d, 3 y) NR/NR 124 R, UR Enema (14), NJ tube (1),Cantor tube (1)

Faust et al [68] 19922001 PMC/CDI 6 6 (100.0) 53 (3774) NR (950 mo) NR/NR NR R (4), B (1), S (1) NR

Abbreviations: CDI, Clostridium difficile infection; IBD, inflammatory bowel disease; NJ, nasojejunal; NR, not reported; PMC, pseudomembranous colitis; S. aureus, Staphylococcus aureus infection. Donor relationship

abbreviations: B, brother; C, unspecified child; D, daughter; F, father; GC, grandchild; H, husband; LA, in-law; P, unspecified parent; R, unspecified relative or family member; S, son; SP, spouse or partner; UR, unrelated

volunteer.a Includes resolution after retreatment for treatment failure.b From Gustafsson et al [21].c By enema.d By Cantor tube.

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from a related donor showed a slightly higher resolution rate

(93%) compared with unrelated donor stool (84%) (Table 2).

Relatives included both family members and spouses or partners.

Where data were available, IMT from a family member showed

87% resolution (34/39 patients) and 8% relapse (2/24 patients),

whereas IMT donated from a spouse or partner showed 96%

resolution (23/24 patients) and 13% relapse (2/15 patients). By

sex, IMT from a male donor showed 86% resolution (12/14

patients), with no relapses, and IMT from a female donor showed

100% resolution (12/12 patients) but 8% relapse (1/12 patients)

(data not shown).

Resolution rates were greater with IMT suspensions prepared

using water (98.5%) than for those prepared with normal saline

(86%); however, with water, the rate of relapse was .2 times

Table 2. Outcomes Achieved in Patients Treated With Intestinal Microbiota Transplantation for Clostridium difficile Infection andRelated Conditions, Excluding Retreatments After Treatment Failure, by Characteristics of the Procedure

Patients with outcome/patients in sample (%)

Procedure characteristics Studies, no. Resolutiona RelapsebDeaths due to

treated condition

Deaths due to

any cause

All procedures 28 284/317 (89.0) 11/284 (3.9) 4/317 (1.3) 13/317 (4.1)

Infusions, no.

1 12 147/168 (87.5) 7/147 (4.8) 3/168 (1.8) 8/168 (4.8)

#3 5 67/70 (95.7) 3/67 (4.5) 0/70 (0.0) 0/70 (0.0)

.3 5 36/40 (90.0) 1/36 (2.8) 1/40 (2.5) 5/40 (12.5)

NR 6 34/39 (87.2) 0/34 (0.0) 0/39 (0.0) 0/39 (0.0)

Instillation methodc

Colonoscope 9 55/62 (88.7) 3/55 (5.4) 0/62 (0.0) 0/62 (0.0)

Enema 11 105/110 (95.4) 5/105 (4.8) 1/110 (0.9) 5/110 (4.5)

Gastroscope or NJ tube 4 55/72 (76.4) 2/55 (3.6) 3/72 (4.2) 7/72 (9.7)

Rectal catheter 2 44/46 (95.6) 0/44 (0.0) 0/46 (0.0) 1/46 (2.2)

.1 method 2 19/21 (90.5) 1/19 (5.3) 0/21 (0.0) 0/21 (0.0)

NR 1 6/6 (100.0) 0/6 (0.0) 0/6 (0.0) 0/6 (0.0)

Donorc

Related 19 195/209 (93.3) 7/195 (3.6) 0/209 (0.0) 3/209 (1.4)

Unrelated 4 21/25 (84.0) 0/21 (0.0) 0/25 (0.0) 1/25 (4.0)

Mixedd 3 57/72 (79.2) 4/57 (7.0) 4/72 (5.6) 9/72 (12.5)

NR 3 11/11 (100.0) 0/11 (0.0) 0/11 (0.0) 0/11 (0.0)

Diluent

Normal saline 20 169/196 (86.2) 5/169 (3.0) 4/196 (2.0) 11/196 (5.6)

Water 1 64/65 (98.5) 5/64 (7.8) 0/65 (0.0) 1/65 (1.5)

Othere 3 31/35 (88.6) 1/31 (3.2) 0/35 (0.0) 1/35 (2.9)

NR 4 20/21 (95.2) 0/20 (0.0) 0/21 (0.0) 0/21 (0.0)

Pre-IMT treatment

Vancomycin or metronidazolef 6 150/164 (91.5) 5/150 (3.3) 3/164 (1.8) 6/164 (3.7)

Antibioticsg and bowel lavage 2 33/35 (94.3) 4/33 (12.1) 0/35 (0.0) 0/35 (0.0)

Otherh 8 43/50 (86.0) 2/43 (4.6) 0/50 (0.0) 3/50 (6.0)

NR 12 58/68 (85.3) 0/58 (0.0) 1/68 (1.5) 4/68 (5.9)

IMT suspension volume, mL

,200 5 32/40 (80.0) 2/32 (6.2) 0/40 (0.0) 3/40 (7.5)

200500 13 98/114 (86.0) 4/98 (4.1) 3/114 (2.6) 5/114 (4.4)

.500 2 107/110 (97.3) 5/107 (4.7) 0/110 (0.0) 1/110 (0.9)

NR 8 47/53 (88.7) 0/47 (0.0) 1/53 (1.9) 4/53 (7.5)

Stool weight, g

,50 9 53/64 (82.8) 2/53 (3.8) 0/64 (0.0) 2/64 (3.1)

$50 7 100/116 (86.2) 1/100 (1.0) 3/116 (2.6) 6/116 (5.2)

NR 12 131/137 (95.6) 8/131 (6.1) 1/137 (0.7) 5/137 (3.6)

Abbreviations: CDI, Clostridium difficile infection; IMT, intestinal microbiota transplantation; NR, not reported.a Resolution was defined as the cessation of symptoms or disappearance of disease without the need for retreatment.b Subset of patients who experienced a return of signs and symptoms.c Patients from the same study are reported in .1 category, so the number of studies do not add up to 28.d Both related and unrelated donors were used.e Other diluents included saline with psyllium (n 5 16), milk (n 5 18), and yogurt (n 5 1).f Vancomycin only (n 5 111), vancomycin and metronidazole (n 5 7), or vancomycin or metronidazole (n 5 46).g Antibiotics not specified.h Other pre-IMT treatments included bowel lavage (n 5 2), nitazoxanide and bowel lavage (n 5 1), unspecified antibiotic therapy (n 5 12), vancomycin andomeprazole (n 5 34), and a-tocopheryl quinone (n 5 1).




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greater (8% vs 3% for saline) (Table 2). Other diluents used to

prepare IMT suspensions included yogurt, milk, and saline

with psyllium. Suspensions prepared with milk resulted in

94% resolution (15/16 patients), and saline with psyllium

resulted in 94% resolution (15/16 patients) and 1 relapse

(7%). The 1 patient treated with a yogurt suspension had

resolution without relapse.

Patients who received both bowel lavage and an antibiotic

before IMT showed the highest relapse rate (12%) (Table 2).

Where treatment before IMT was classified as other, all fail-

ures occurred in patients who received vancomycin and ome-

prazole (a proton pump inhibitor) before IMT [48, 55, 58].

Thirty-four patients in this group received vancomycin and

omeprazole, with 6 failures (18%) (data not shown).

Resolutions increased with the volume of IMT given (97%

given .500 mL vs 80% given ,200 mL). Where data were

reported, there was very little difference in resolution rates when

more donor stool (in grams) was used to prepare the IMT

suspension. However, the relapse rate was 4 times greater when

,50 g of stool was used (4% vs 1% for $50 grams) (Table 2).

Of the patients who received retreatment due to failure or

relapse, 87.5% (14/16 patients) experienced resolution. Thirteen

deaths (4%) occurred during follow-up, of which 3, all from a

single study [17], were attributed to CDI (1%). Adverse events

included upper gastrointestinal hemorrhage (n 5 1) [55], IBS

symptoms (n 5 4) [51], infectious IBS symptoms (n 5 1) [59],

constipation (n 5 1) [56], and signs of irritable colon (n 5 1)

[19]. None of these could be directly attributed to IMT (data not

shown).

DISCUSSION

We have summarized the literature describing patients treated

with IMT for recurrent CDI and PMC. Evidence from 317 pa-

tients across 27 case series and reports suggests that IMT is

a highly effective therapy for these disorders when standard

treatments have failed. IMT resulted in resolution for 92% of

patients (89% after a single treatment). Relapses and deaths after

IMT were relatively uncommon. When case data were summa-

rized by the characteristics of the procedure, instillation by gas-

troscope or NJ tube seemed least effective, and stool from a related

donor was most effective. The effectiveness of water versus saline

suspensions is difficult to interpret because water suspensions

resulted in more frequent resolution but also more relapses;

however, these were all reported from a single study. A possible

dose response was also observed for resolution without retreat-

ment in patients who received increasing volumes of IMT sus-

pension. The slightly lower resolution rate in patients given 1

infusion in a single treatment may be due to the lower rate of

resolution in patients infused by gastroscope in 1 study (73%), all

of whom received 1 infusion [17]. Excluding this study, resolution

occurred in 91% of patients who received 1 infusion. Thus, out-

come rates did not appear to vary with number of infusions given.

Although the exact mechanism of action for IMT therapy is

unknown, it is believed to restore the composition and function of

the intestinal microbiota in diseased patients [2]. Various reports

have documented changes to the intestinal microbiota after IMT

[44, 48, 61], and the microbiota of treated patients typically has

been shown to resemble that of the donor after infusion [44, 61].

Further support for the efficacy of this procedure is provided

by its use in the treatment of other gastrointestinal disorders.

Our literature search identified 4 such reports (13 patients

treated for inflammatory bowel disease and 5 for IBS) [4144].

These studies reported 100% resolution and no relapses or

deaths. However, 89% of these patients received .3 infusions,

and 56% were infused with $200 milliliters of fecal suspension.

The effectiveness of IMT is also supported by the successful use

of cultured bacterial suspensions in the treatment of recurrent

CDI and other gastrointestinal disorders [34, 48].

Other alternatives to standard therapies, such as probiotics,

toxin-binding molecules, immunoglobulin, and C. difficile vac-

cination remain unproved. Evidence for the use of probiotics in

the treatment of CDI is conflicting [6971]. Only Saccharomyces

boulardii has been found to reduce the absolute risk of re-

currence by 30%33% [72, 73] and only in combination with

antibiotics. Toxin-binding molecules are designed to target

specific C. difficile toxins and block their pathologic effects [74].

One such treatment, tolevamer, has been shown to reduce the

absolute risk of CDI recurrence by 20% and 24% compared with

vancomycin and metronidazole but was found to be inferior to

both in treating primary CDI (46% cure rate for tolevamer vs

81% and 72% for vancomycin and metronidazole, respectively)

[74]. The administration of antibodies against C. difficile or its

toxins is another alternative treatment approach. RCTs have

found monoclonal antibodies to be comparable to metronida-

zole in preventing recurrence (44% and 45%, respectively) [75]

and have found intravenous immunoglobulin to reduce the

absolute rate of recurrence by 18% in patients who were re-

ceiving metronidazole or vancomycin in parallel [76]. However,

immunoglobulin is more costly than other therapies [31]. The

evidence supporting vaccination for the prevention of CDI re-

currence is limited (3/3 patients were cured with no recurrence

after vaccination with a C. difficile toxoid A and B vaccine) [7].

Fidaxomicin was also shown to be not inferior to vancomycin in

a recent RCT [9].

LimitationsClassification of variables associated with IMT procedure was

not standard across studies; therefore, operational definitions

were defined a priori for data abstraction. However, publications

often did not report data on these variables. Data on weight of

stool used were not reported for 43% of patients (12 studies),




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and data on pre-IMT treatment were not reported for 21%

(12 studies) (Table 2). The volume of suspension and number of

infusions given were also not reported for .10% of patients

(6 and 8 studies, respectively).

Most patients also received treatment or preparation with an-

other procedure (eg vancomycin or bowel lavage) before IMT was

performed, making it difficult to estimate the effect of IMT alone.

Available data suggest that resolution rates may be slightly higher

in patients treated with vancomycin, metronidazole, or un-

specified antibiotics with bowel lavage before IMT (92%) and

lower in patients treated with vancomycin and omeprazole (82%).

In addition, relapses may be due to reinfection with a new strain

rather than relapse of infection with the same strain of C. difficile

[14]. Distinguishing between these 2 occurrences after IMT

therapy is of clinical relevance, but this distinction was made only

in 1 study [62] and could not be explored in our analysis.

A final limitation is the heterogeneity of the populations trea-

ted. This analysis included patients from 8 countries, including

Australia, North America, and Europe, treated over a period of 53

years. The variability in outcomes across procedures may be partly

explained by differences in the underlying populations studied

and by the small number of patients in some categories. However,

methods for pooling data and for a formal exploration of het-

erogeneity using case reports are very limited [77] and could not

be applied to these studies, limiting our analysis to descriptive

statistics. Methods to assess study quality or publication bias in

case reports are also unavailable. It is possible that cases success-

fully treated with IMT were more likely to be published. These

study designs may also be less subject to peer review, which poses

another possible source of bias.

Despite these limitations, these data suggest that IMT may be

a highly effective and safe therapy for recurrent CDI and PMC

when standard treatments have failed. IMT is also a more readily

accessible and less costly procedure than some standard or other

alternative therapies [28]. There are also biologically plausible

explanations for its action. However, differences in the IMT pro-

cedure may influence resolution rates. Instillation by gastroscope

or NJ tube may be less effective than other methods. Relatives of

patients could be given priority as potential stool donors. One

infusion may be sufficient, depending on the route. Physicians

who are interested in applying this procedure as an alternative

therapy should be guided by evidence from these case reports.

However, published case reports can provide very biased evidence

of treatment efficacy, and better designed studies, such as RCTs,

are necessary to confirm the efficacy of this therapy and define best

practices for its use, including standards for pre-IMT treatment.

Supplementary Data

Supplementary materials are available at Clinical Infectious Diseases

online (http://www.oxfordjournals.org/our_journals/cid/). Supplementary

materials consist of data provided by the author that are published to

benefit the reader. The posted materials are not copyedited. The con-

tents of all supplementary data are the sole responsibility of the authors.

Questions or messages regarding errors should be addressed to the author.

Notes

Acknowledgments. The authors would like to thank Deanna Cowan,

librarian at the McGill University Life Sciences Library for her expert as-

sistance with the electronic literature search. We would also like to thank

Kerstin Tiedemann for her assistance in abstracting the nonEnglish-lan-

guage publications.

Financial support. This work was supported by funds from the Ca-

nadian Institutes of Health Research (CHM-94228 to A. R. M.).

Potential conflicts of interest. All authors: No reported conflicts.

All authors have submitted the ICMJE Form for Disclosure of Potential

Conflicts of Interest. Conflicts that the editors consider relevant to the

content of the manuscript have been disclosed.

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